Abstract

The pathophysiology of Parkinson's disease (PD) has long been attributed to dopamine (DA) loss in the striatum. However, it remains unclear whether simple underactivation of striatal DA receptors is sufficient to induce parkinsonian signs. To test this hypothesis, we performed unilateral infusions of cis-flupenthixol (cis-flu; D1/D2 antagonist) into the macaque putamen, while the macaque performed a reaching task. Twenty-six cis-flu and three saline infusions were performed across three hemispheres in two macaques. Neuronal and local field potential activity was recorded simultaneously from cortex, globus pallidus externa (GPe), and globus pallidus interna (GPi) during most infusions. The reaching task required each macaque to make visually-cued reaching movements to a target for a reward. The macaque was then required to return its hand to a home position without external cues. Injection-related slowing of movement initiation or execution was thought to reflect akinetic- or bradykinetic-like effects, respectively. Following 8/26 cis-flu infusions, macaques exhibited a marked slowing in the initiation of self-generated return movements (95% increase). This was the most severe behavioral effect of cis-flu infusions. The initiation and execution of externally-cued movements were also prolonged following 9/26 and 6/26 injections, but only by 20% and 15% respectively. In general, akinetic-like effects occurred twice as often as bradykinetic-like effects (p<0.05, 2= 4.1). Interestingly, akinetic and bradykinetic effects could be elicited independently. In addition to affecting behavior, intrastriatal DA receptor blockade also reduced resting and peri-movement activity in the cortex and suppressed resting GPe activity. Burstiness, synchrony, and oscillatory activity in cortex were increased following intrastriatal DA receptor blockade as well. Oscillatory activity was also increased in the GPe and GPi. In conclusion, suppression of striatal DA activity was sufficient to induce akinetic-like signs, most severely affecting movement initiation during self-generated movements. Furthermore, distinct parkinsonian-like signs could be elicited independently, suggesting that separate signs may have unique pathophysiologic substrates. Intrastriatal DA receptor blockade also induced changes in cortical and BG activity that were consistent with findings in the parkinsonian state. Interestingly, many of these neuronal activity changes were specific to cortex, implicating an important role for cortical activity in the development of akinetic parkinsonian signs.